Drug Treatment of Cardiac Failure

Heart Failure

chronic or acute state resulting from failure of the heart to meet oxygen demands of the body; heart does not have enough strength to pump blood

Symptoms of Heart Failure

shortness of breath, swollen feet and ankles, abdominal swelling, sudden weight gain, dizziness, heart palpitations

Therapeutic goals in heart failure treatment

reverse signs and symptoms of heart failure to improve quality of life, arrest ventricular remodeling, increase survival; when severe there is not cure, only prevention and slowing progression

Class I - asymptomatic Heart Failure

failure is associated with no limitations on ordinary activities, but are revealed during exercise

Class II - compensated heart failure

characterized by slight limitation on ordinary activity, results in fatigue and palpitations

Class III - decompensated heart failure

mild symptoms at rest but fatigue with less than ordinary physical activity

Class IV - refractory heart failure

associated with marked symptoms event at rest despite dietary modification, maximal medical therapy needed, patients require frequent hospitalizations and may end up on the transplant list

3 main adaptive responses in heart failure

1. activaton of RAAS system

2. Increase of BP and PVR to attempt to restore reperfusion

3. increase in inefficient heart contractility and rate (quivering) in an attempt to restore cardiac efficiency

Positive Inotropic Drugs

Drugs intended to increase contractility of heart

Digitalis glycosides (digoxin)

extracted from leaves of foxglove, increases cardiac output by increasing force of heartbeat and slowing heart rate; has beneficial neurohormonal effects such as RAAS and noradrenaline being reduced, lowers heart rate (anti-arhythmic) but pro-arhythmic at higher doses, improves symptoms, decreases hospitalizations, no effect on long term survival, narrow therapeutic index

adverse effects of digoxin

neurotropenia, dysrhythmias in 30-40%, digitalis toxicity(altered vision)in 15-90%, GI effects in 57-100% (anorexia, nausea, vomiting, diarrhea), neurological and neuromuscular effects in 30-90%,

Mechanism of digoxin

blocks Na+/K+ ATPase, less expulsion of cytosolic calcium ions by Na+/Ca+ exchanger, increased elevation of cytosolic calcium from sarcoplasmic reticulum, increases contractility

Kinetics of digoxin

orally active: 60-80% bioavailability with half life of 36 hours; has plasma and tissue protein binding affecting drug interactions, useful at 1-2.6 nM, lower end of range used, toxicity is patient specific

beneficial effects of digitalis in HF

increased force of contraction, increased cardiac output and stroke volume, decreased heart rate, decreased blood volume decreased heart size and wall tension, decreased venous presure and edema, increased cardiac efficiency

Nitrates

metabolized into nitric oxide which causes vascular smooth muscle relaxation by inhibiting phosphorylation of myosin→ decreases cardiac work and oxygen demand; used in acute HF, angina, and malignant hypertension when the patient is intolerant to ace inhibitors

Positive Effects of nitrates

venorelaxation and reduction in central venous pressure decreases preload; relaxation of large arteries reduces central aortic pressure and cardiac afterload; coronary vasodilation increases coronary flow

side effects of nitrates

postural hypotension, headache, dizziness, reflex tachycardia, tolerance to effects

Nitroglycerin

well absorbed from mouth BUT NOT FROM GUT, so mainly administered with sublingual spray; transdermal, topical, IV and oral are also available; fast-acting, short-lasting; spray peaks in 30 seconds and lasts three to five minutes due to short half life; tablets peak in four minutes with a half life of 30 minutes; used in emergency/acute events

Isosorbide mononitrate

sublingual or oral, slower onset of action and longer acting (4 hours) compared to nitroglycerin; taken 2 times daily for prophylaxis

Beta Blockers

prevents catecholamines from binding beta-receptors, recommended for majority of heart failure patients, counteracts harmful effects of sustained SNS activation, beneficial effects in heart failure on LV remodeling and reduction of arterial pressure, caution when using with asthma or diabetes

Angiotension receptor antagonists

block AT1 receptor, used as a alternative to Ace inhibitors because they are better tolerated as they do not degrade bradykin, more affordable than ACEi, AT1 receptor antagonist that acts on arterial smooth muscle and adrenal glands; used in patients intolerant to ACEis, same side effects as ACEis with NO COUGH

Ace Inhibitors

enzyme inhibitor that mimics angiotensin I and blocks effects of angiotensin II; lowers peripheral resistance and decreases blood volume; side effects of hyperkalemia, hypotension, angiodema, dry cough and renal impairment

ACEis + ARAs in HF

currently being evaluated. Decrease hospitalizations but no decrease in mortality

effects of antiotension II

Increase in PAI-1/thrombosis, platelet aggregation, superoxide production, Vascular remodeling [increased collagen formation, increase vSMC growth, increased myocyte growth], increased endothelin, increased vasopressin, increased aldosterone, activation of SNS, abnormal vasoconstriction

Aldosterone in HF

is a mineral corticoid produced by adrenal cortex; mineral corticoid receptors regulate Na+ retention (volume overload), K+ and Mg+ loss (arythmias), mycardial fibrosis(pathologic remodeling and left ventricle hypertrophy), and endothelial cell dysfunction (decreased arterial compliance, pathological remodeling and abnormal ventricular-arterial coupling)

aldosterone inhibitors

K+ sparing diuretics, competitive antagonist against aldosterone receptor, block aldosterone binding mineralcorticoid receptor in kidneys, heart, blood vessels and brain, blockade of aldosterone at distal renal tubule( increased Na+/Cl- and water exretion, K+ retention, activation of fibroblasts)

side effects of aldosterone inhibitors

serious hyperkalemia, renal insufficiency, breast pain, rash

spironalactone

aldosterone inhibitor associated with a decrease in mortality of over 30% in late stage III and stage IV patients

eplerone

aldosterone inhibitor associated with reduced death from CV events or hospitalization by 13% and decrease in sudden cardiac death by 21%

Managing volume oveload

fluid restriction, salt restriction, monitor weight/fluid balance, patient education, diuretics (loop or thiazide), improve cardiac pump function to increase cardiac output

diuretics

used for management of edema associated with CV, HF, HTN, nephrotic syndrome, and glaucoma; goal is to increase excretion of salt and water; most diuretics inhibit reabsorption from nephron into kidneys and cause an increase of excretion of Na+ in urine

efficacy of diuretics in HF

in the short term, decrease pulmonary congestion, peripheral edema, and body weight; in the intermediate, improves cardiac function, symptoms, and exercise tolerance; in the long term there are incomplete studies on mortality

NOT used alone in HF, prescribed to all patients with evidence of fluid retention